A Targeted Genetic Association Study of the Rare Type of Osteomyelitis

Abstract

Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.

Shotgun metagenomic analysis of saliva microbiome suggests Mogibacterium as a factor associated with chronic bacterial osteomyelitis

“…The diagnostic criteria for CNO were consistent with those used in our previous study [ 5 ]: 1) recurrent pain and swelling; 2) radiographic appearance of a mixed pattern of sclerosis and osteolysis, and uptake of scintigraphic agents (such as technetium 99 m) in the jawbone; 3) limited or no response to antibiotic treatment; and 4) increased bone resorption and deposition, along with varying degrees of bone sclerosis and medullary fibrosis, without suspicion of malignancy.…”

“…The influence of genetic and immunological backgrounds on CNO is not completely understood. A recent study defined the alleles of all 35 human leukocyte antigen (HLA) loci and haplotype structures of the killer cell immunoglobulin-like receptor (KIR) region and identified a specific amino acid substitution in HLA-C in combination with the telomeric KIR genotype, which had a significantly higher frequency in the CNO population compared to the control population [ 5 ]. Another recent study investigated CNO based on whole blood RNA sequencing (>6 Gb per sample) of 11 patients and 9 healthy controls in Japan and employed a recently developed method suitable for small datasets.…”

Whole blood transcriptome profiling identifies gene expression subnetworks and a key gene characteristic of the rare type of osteomyelitis

“…We used the same diagnostic criteria as in our previous study [ 3 ]. The criteria were as follows: 1) recurrent pain and swelling; 2) radiographic appearance of a mixed pattern of sclerosis and osteolysis and uptake of scintigraphic agents, such as technetium 99 m, in the region of the jawbone; 3) little or no benefit from antibiotic treatment; and 4) increased bone resorption and deposition, and varying degrees of bone sclerosis and medullary fibrosis with no suspected malignancy.…”

“…Little is known about the dynamics of inflammatory responses in CNO or how the genetic and immunological backgrounds of patients influence the disease. A clue in this regard has been provided by a recent study [ 3 ] that aimed to overcome the limitations of traditional exon typing in the human leukocyte antigen ( HLA ) gene region, based on latest sequencing technologies [ 4 ]. The recent study simultaneously determined the alleles of all 35 HLA loci and haplotype structures of the killer cell immunoglobulin-like receptor (KIR) region and identified a specific amino acid substitution in HLA-C, in combination with the telomeric KIR genotype, which has a significantly higher frequency in the CNO population than in the control population [ 3 ].…”

Chronic recurrent multifocal osteomyelitis. A narrative and pictorial review

“…FBLIM1 gene encodes filamin binding lin-11, islet-1, mec-3 (LIM) protein (37,38). More recently, Yahara et al (39) have indicated that the interaction between some haplotypes of killer cell immunoglobulin-like receptors and the human leukocyte antigen (HLA) may be critical. This interaction would be able to determine the HLA instability leading inexorably to autoimmunity in CRMO.…”